Preparation of intedanib of formula 1 is first described by the patent application WO0127081 (Scheme 1).

In this synthesis, methyl oxindole-6-carboxylate is converted to methyl (E)-1-acetyl-3-(ethoxyphenylmethylene)-oxindole-6-carboxylate of formula Et-2 with the yield of 61%. The compound Et-2 subsequently reacts with N-(4-aminophenyl)-N,4-dimethyl-1-piperazine acetamide and then, without isolation of the intermediate, with piperidine, producing intedanib of formula 1. The yield of this reaction step is not mentioned.
A modification of the above mentioned preparation of intedanib 1 was published in J. Med. Chem. 2009, 52, 4466-4480 (Scheme 2).

There, methyl oxindole-6-carboxylate is first converted to methyl 1-acetyl-oxindole-6-carboxylate of formula 3 with the yield of 73%. Intermediate 3 is then converted to methyl (E)-1-acetyl-3-(methoxyphenylmethylene)-oxindole-6-carboxylate of formula 2 without the yield being mentioned. Compound 2 subsequently reacts with N-(4-aminophenyl)-N,4-dimethyl-1-piperazine acetamide and then, without isolation of the intermediate, with piperidine, producing intedanib of formula 1. The yield of this reaction step is 77%. A weak point of the above mentioned synthesis is a relatively low yield of compound 3 in the first step. A significant drawback of the above mentioned synthesis is the use of the toxic dimethyl formamide as the solvent and of the toxic piperidine as the base in the last step.
A preparation method of intedanib of formula 1 suitable for industrial production is described in the patent application WO2009071523 (Scheme 3).
Methyl oxindole-6-carboxylate is first converted to methyl 1-chloroacetyl-oxindole-6-carboxylate with the yield of 93.5%. It is followed by a reaction of this compound with trimethyl orthobenzoate, producing methyl (E)-1-chloroacetyl-3-(methoxyphenylmethylene)-oxindole-6-carboxylate with the yield of 91.7%. Then, the chloroacetyl group is removed, producing methyl (E)-3-(methoxyphenylmethylene)-oxindole-6-carboxylate with the yield of 94.6% and, finally, a reaction of this compound with N-(4-aminophenyl)-N,4-dimethyl-1-piperazine acetamide provides intedanib of formula 1 with the yield of 89%. A weak point of the above mentioned synthesis is the use of the expensive chloroacetanhydride as the acylating agent in the first step. A considerable disadvantage of the above mentioned synthesis is the formation of the toxic methyl chloroacetate as a side product in the third step.